TY - JOUR
T1 - Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis
T2 - Novel role for an old enemy
AU - Coffey, J. Calvin
AU - Wang, Jiang Huai
AU - Smith, Myles J.F.
AU - Laing, Alan
AU - Bouchier-Hayes, David
AU - Cotter, Tom G.
AU - Redmond, H. Paul
PY - 2005/6/3
Y1 - 2005/6/3
N2 - Tumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110γ and p85α class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.
AB - Tumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110γ and p85α class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.
UR - http://www.scopus.com/inward/record.url?scp=20444380697&partnerID=8YFLogxK
U2 - 10.1074/jbc.M414696200
DO - 10.1074/jbc.M414696200
M3 - Article
C2 - 15741161
AN - SCOPUS:20444380697
SN - 0021-9258
VL - 280
SP - 20968
EP - 20977
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 22
ER -